title: Tumor endothelial cell-specific drug delivery system using apelin-conjugated liposomes.
abstract: BACKGROUND
  A drug delivery system specifically targeting endothelial cells (ECs) in tumors is required to prevent normal blood vessels from being damaged by angiogenesis inhibitors. The purpose of this study was to investigate whether apelin, a ligand for APJ expressed in ECs when angiogenesis is taking place, can be used for targeting drug delivery to ECs in tumors.
  
  
  RESULTS
  Uptake of apelin via APJ stably expressed in NIH-3T3 cells was investigated using TAMRA (fluorescent probe)-conjugated apelin. Both long and short forms of apelin (apelin 36 and apelin 13) were taken up, the latter more effectively. To improve efficacy of apelin- liposome conjugates, we introduced cysteine, with its sulfhydryl group, to the C terminus of apelin 13, resulting in the generation of apelin 14. In turn, apelin 14 was conjugated to rhodamine-encapsulating liposomes and administered to tumor-bearing mice. In the tumor microenvironment, we confirmed that liposomes were incorporated into the cytoplasm of ECs. In contrast, apelin non-conjugated liposomes were rarely found in the cytoplasm of ECs. Moreover, non-specific uptake of apelin-conjugated liposomes was rarely detected in other normal organs.
  
  
  CONCLUSIONS
  ECs in normal organs express little APJ; however, upon hypoxic stimulation, such as in tumors, ECs start to express APJ. The present study suggests that apelin could represent a suitable tool to effectively deliver drugs specifically to ECs within tumors.
authors.affiliation: Department of Signal Transduction, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, Japan.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Kawahara
authors.forename: Hisamichi
authors.initials: H
authors.lastname: Naito
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Takara
authors.forename: Taku
authors.initials: T
authors.lastname: Wakabayashi
authors.forename: Hiroyasu
authors.initials: H
authors.lastname: Kidoya
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Takakura
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000378:metabolism; D000075244:Apelin Receptors; D045744:Cell Line, Tumor / Q000473:pathology; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D004354:Drug Screening Assays, Antitumor; D042783:Endothelial Cells / Q000378:metabolism*; D005260:Female; D036341:Intercellular Signaling Peptides and Proteins / Q000008:administration & dosage* / Q000378:metabolism; D008081:Liposomes; D008546:Melanoma, Experimental / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D041681:NIH 3T3 Cells; D009368:Neoplasm Transplantation; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D000075244:Apelin Receptors; C491285:Aplnr protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; D008081:Liposomes; D043562:Receptors, G-Protein-Coupled; C585958:apelin-14